Discovery of BMS-846372, a Potent and Orally Active Human CGRP Receptor Antagonist for the Treatment of Migraine

被引：31

作者：

Luo, Guanglin ^{[1
]}

Chen, Ling ^{[1
]}

Conway, Charles M. ^{[1
]}

Denton, Rex ^{[1
]}

Keavy, Deborah ^{[1
]}

Gulianello, Michael ^{[1
]}

Huang, Yanling ^{[1
]}

Kostich, Walter ^{[1
]}

Lentz, Kimberley A. ^{[1
]}

Mercer, Stephen E. ^{[1
]}

Schartman, Richard ^{[1
]}

Signor, Laura ^{[1
]}

Browning, Marc ^{[1
]}

Macor, John E. ^{[1
]}

Dubowchik, Gene M. ^{[1
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Mol Sci & Candidate Optimizat, Neurosci Biol, Wallingford, CT 06492 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 04期

关键词：

migraine; CGRP; CGRP receptor; antagonist; GENE-RELATED-PEPTIDE; HEADACHE; TELCAGEPANT; COMPLEXES; SYSTEM;

D O I：

10.1021/ml300021s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.

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收藏

页码：337 / 341

页数：5

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